4-cyclohexylvulpinic acid derivatives

ABSTRACT

4-CYCLOHEXYLVULPINIC ACID DERIVATIVES HAVING ANTI-ARTHRITIC ACTIVITY PREPARED BY ALCOHOLYSIS OF THE CORRESPONDING 4-CYCLOHEXYLPULVINIC ACID DILACTONE.

United States Patent 3,752,829 4-CYCLOHEXYLVULPINIC ACID DERIVATIVESBlaine M. Sutton, Hatboro, Pa., assignor to Smith Kline & FrenchLaboratories, Philadelphia, Pa.

No Drawing. Continuation-in-part of abandoned application Ser. No.188,439, Oct. 13, 1971. This application Aug. 21, 1972, Ser. No. 282,534

Int. Cl. C07d /06 US. Cl. 260-343.6 11 Claims ABSTRACT OF THE DISCLOSURE4 cyclohexylvulpinic acid derivatives having anti arthritic activityprepared by alcoholysis of the corresponding 4-cyclohexylpulvinic aciddilactone.

CHaO-C=0 OR B,

R represents hydrogen, acrylyl, methacrylyl, dimethacrylyl, crotonyl orcinnamoyl;

R represents hydrogen, chlorine, bromine, fluorine, lower alkyl of from1 to 4 carbon atoms, lower alkoxy of from 1 to 4 carbon atoms,dimethoxy, trimethoxy, or trifluoromethyl; and

R represents hydrogen, chlorine, bromine, or fluorine.

Preferably the compositions of this invention comprise a compound of theabove formulas when R is hydrogen, R is hydrogen, chlorine, fluorine,methyl, methoxy, or ethoxy, and R is hydrogen or chlorine. Mostadvantageously, R is hydrogen and R is hydrogen or ethoxy, and R ischlorine.

The novel 4-cyclohexylvulpinic acid derivatives are prepared accordingto the following synthetic procedure:

EHCN

3,752,829 Patented Aug. 14, 1973 ice onion R1 11* Formula III and AcylHalide Separated by Fractional Pyridine Crystallization from CtHs andCHZOH CH30C=O OR in which R, R and R are as defined for the aboveformulas. Thus a phenylacetonitrile is condensed with ethyl oxalate inan alcoholic solution of an alkali metal lower alkoxide, such as sodiummethoxide or ethoxide to give the ethyl 3-cyano-3-phenylpyruvate. Thiscompound is further condensed with a 4-cyclohexylphenylacetonitrile inan alcoholic solution of an alkali metal lower alkoxide, such as sodiummethoxide or ethoxide to yield the 2-(4-cyclohexylphenyl)-5-phenyl 3,4dioxoadiponitrile. The above condensations may also be carried out usinga metal hydride, such as sodium hydride, in diglyme. The adiponitrilederivative is refluxed for a short period of time, for example one ortwo hours, in an aqueous acid solution such as water/ glacial aceticacid/ concentrated sulfuric acid mixture and the resulting pulvinic acidis refluxed with acetic anhydride to furnish the corresponding pulvinicacid lactone of Formula III above. The dilactone is ring opened to the4-cyclohexylvulpinic acid by brief refluxing with methanol containing a;mineral acid such as hydrochloric acid. The vulpinic acid derivative isthen heated with the appropriate acyl halide, preferably acyl chloride.The reaction is advantageously carried out in a nonreactive organicsolvent such as chloroform in the presence of pyridine to yield the,desired ester of 4-cyclohexylvulpinic acid.

In the above synthetic sequence, the ring opening of the dilactone ofFormula III gives a mixture of positional isomers, namely compounds ofFormula I and compounds of the following formula:

The ratio of isomers obtained is variable. The isomers can be separatedby fractional crystallization and/or chromatographic procedures. Theiridentity is determined from the nuclear magnetic resonance patterns ofthe aromatic protons. This identification can be confirmed bydegradative ozonolysis.

The anti-arthritic activity of the compounds of this invention ismeasured by their ability to inhibit adjuvant arthritis in rats. Thenovel compounds of this invention produce marked inhibition of thedevelopment of adjuvant arthritis in rats at a daily oral dose of 16 mg.per kilogram of body weight. Adjuvant arthritis in rats is produced by asingle injection of 0.75 mg. of Mycobacterium butyricum suspended inwhite parafiin (N.F.) into a hindpaw (left footpad). The injected pawbecomes inflamed and reaches a maximum volume in 3-5 days (primarylesion). The animals exhibit a decrease in body weight gain during thisinitial period. Adjuvant arthritis (secondary phase) occurs after adelay of approximately 10 days and is characterized by inflammation ofthe non-injected sites (right hind leg), decrease in body weight gainand further increases in the volume of the injected hind leg. Thecompounds of Formulas I and H administered in the doses described abovebeginning on the day of adiuvant injection and continuing for 17 daysthereafter, exclusive of days 4, 5, 11, and 12, protect the animalsagainst development of both primary and secondary lesions of adjuvantarthritis.

The compounds of this invention may be administered orally orparenterally in conventional dosage unit forms such as tablets,capsules, injectables or the like,,by incorporating the appropriate doseof a compound of Formulas I and H with carriers according to acceptedpharmaceutical practices. Preferably the compound is administered orallyto an animal organism in a tablet or capsule comprising an amountsufficient to produce anti-arthritic activity. Each dosage unit willcontain the active medicament in an amount of about 10 mg. to about 50mg. Advantageously equal doses will be administered 1 to 3 times dailywith the daily dosage regimen being about 10 mg. to about 150 mg.

The pharmaceutical carrier employed may be, for example, either a solidor liquid. Exemplary of solid carriers are lactose, terra alba, sucrose,talc, gelatin, agar, pectin, acacia, magnesium stearate, stearic acidand the like. Exemplary of liquid carriers are syrup, peanut oil, oliveoil, water and the like. Similarly the carrier or diluent can includeany time delay material well known to the art, such as glycerylmonostearate or glyceryl distearate alone or with a wax.

A wide variety of pharmaceutical forms can be employed. Thus, if a solidcarrier is used the preparation can be tableted, placed in a hardgelatin capsule in powder or pellet form, or in the form of a troche orlozenge. The amount of solid carrier will vary widely but preferablywill be about 25 mg. to about 1 g. If a liquid carrier is used, thepreparation will be in the form of a syrup, emulsion, soft gelatincapsule, sterile injectable liquid such as an ampule, or an aqueous ornonaqueous liquid suspension.

The following examples are not limiting but are illustrative ofcompounds of this invention and the procedures for their preparation.Other variations of this invention will be obvious to those skilled inthe art.

EXAMPLE 1 A mixture of 117.1 g. of phenylacetonitrile and 326 ml. ofethyl oxalate is added to an ethanol solution of sodium ethoxide(prepared by dissolving 23.8 g. in 500 ml. of absolute ethanol) andrefluxed two hours. After cooling, diluting with 2500 ml. of water andextracting with ether, the solution is acidified with acetic acid. Thesolid is removed and washed with water to give ethyl3-cyano-3-phenylpyruvate, M.P., 127129 C.

Ethyl 3-cyano-3-phenylpyruvate (6.95 g.) is slowly added to a mixture of7.45 g. of 3-chloro-4-cyclohexylphenylacetonitrile and 9.54 g. of sodiumhydride in 20 ml. of diglyme at a temperature of -5 to 0 C. The mixtureis stirred at room temperature overnight, diluted with 150 ml. of waterand extracted with ether. The

aqueous layer is acidified with acetic acid to yield 2-(3'-chloro-4'-cyclohexylphenyl)-5-phenyl 3,4 dioxoadiponitrile as an orangesolid, M.P. 218 C. (d.).

A mixture of 10.3 g. of 2-(3-chloro-4-cyclohexylphenyl) 5 -phenyl 3,4dioxoadiponitrile in 75 ml. of water, ml. of glacial acetic acid and 50ml. of concentrated sulfuric acid is refluxed for one hour. Thesuspension is cooled, poured onto 900 ml. of ice water and the solidremoved and washed to give 3'-chloro-4'-cyclohexylpulvinic acid, M.P.212-2l7 C.

3'chloro-4-cyclohexylpulvinic acid (7.6 g.) is refluxed in ml. of aceticanhydride for 15 minutes. The cooled solution is stirred into 500 ml. ofice and water and the oily mass crystallized by stirring in 250 ml. ofethanol. The yellow solid is removed, washed with ethanol and dried toyield 3'-chloro-4'-cyclohexylpulvinic acid lactone, M.P. 178-179' C.

A mixture of 5.0 g. of the pulvinic acid lactone, in 600 ml. of methanolcontaining 10 ml. of hydorchloric acid (3 6%) is refluxed 1 hour forminga yellow solution. The reaction mixture is concentrated to ml. underreduced pressure, cooled and the crystallized solid, 3-chloro-4'-cyclohexylvulpinic acid, is washed and dried, M.P. l87 C.

Work up of the methanol filtrate and crystallization from benzene andmethanol yielded 3-chloro-4-cyclohexylvulpinic acid.

EXAMPLE 2 Acrylyl chloride, 5 ml., is added to a solution of 4.38 g. of3'-chloro-4'-cyclohexylvulpinic acid (as prepared in Example 1) in 25ml. of chloroform containing 1 ml. of pyridine and refluxed for fiveminutes. The reaction mixture is then concentrated, washed andrecrystallized to yield acrylyl 3'-chloro-4'-cyclohexylvulpinic acid.

EXAMPLE 3 By employing the procedure set forth in Example 1, thefollowing starting materials are substituted for phen ylacetonitrile:

(a) p-chlorophenylacetonitrile (b) m-methoxyphenylacetonitrile (c)o-fluorophenylacetonitrile (d) 3,4,5-trirnethoxyphenylacetonitrile (e)m-trifluoromethylphenylacetonitrile followed by reaction with3-chloro-4-cyclohexylphenylacetonitrile and the subsequent syntheticsteps there is prepared respectively:

(a) 4-chloro-3-ch10ro-4'-cyclohexylvulpinic acid (b)3-methoxy-3'-chloro-4-cyclohexylvulpinic acid (0)2-fluoro-3'-chloro-4-cyclohexylvulpinic acid (d)3,4,5-trimethoxy-3'-chloro-4'-cyclohexylvulpinic acid (e)3-trifluoromethy1-3'-chl0ro-4'-cyclohexylvulpinic acid.

EXAMPLE 4 Methacrylyl chloride, 5 ml., is added to a solution of 4.75 g.of 4-chloro-3'-chloro-4'-cyclohexylvulpinic acid (as prepared in Example3) in 30 ml. of chloroform containing 1 ml. of pyridine and refluxed forlive minutes. The reaction mixture is then concentrated, washed andrecrystallized to yield methacrylyl 4-chloro-3-chloro-4'-cyclohexylvulpinic acid.

EXAMPLE 5 Following the procedures outlined in Example 1, 4-cyclohexylphenylacetonitrile is reacted with ethyl 3-cyano-3-phenylpyruvate and the subsequent synthetic steps yield amixture of 4'-cyclohexylvulpinic acid and 4- cyclohexylvulpinic acid.The isomers are then crystallized from methanol and benzene to firstyield 4'-cyclohexylvulpinic acid. Evaporation of the solvent and furthercrystallization from methanol-benzene yields the 4*cyclohexylvulpinicacid.

The sucrose, calcium sulfate and vulpinic acid are thoroughly mixed andgranulated with hot 10% gelatin solution. The wetted mass is passedthrough a #6 mesh screen directly onto drying trays. The granules aredried at 120 C. and passed through a #20 mesh screen, mixed with thestarch, talc and stearic acid, and compressed into tablets.

EXAMPLE 7 Ingredients: Mg. capsule 3-fluoro-4'-cyclohexylvulpinic acid50 Magnesium stearate 5 Lactose 350 The above ingredients are screenedthrough a #40 mesh screen, mixed and filled into #0 hard gelatincapsules.

EXAMPLE 8 By following the procedures outlined in Example 1 andemploying p-ethoxyphenylacetonitrile in the initial reaction to obtainethyl-3-cyano-3-(p-ethoxyphenyD-pyruvate followed by reaction with4-cyclohexylphenylacetonitrile and the subsequent synthetic steps, thereis prepared 4-ethoxy-4'-cyclohexylvulpinic acid.

What is claimed is:

1. A chemical compound selected from the formulas:

and

R1 CH30G=O OR wherein: R is hydrogen, acrylyl, methacrylyl,dimethylacrylyl, crotonyl or cinnamoyl; R is hydrogen, chlorine,bromine, fluorine, lower alkyl of from 1 to 4 carbon atoms, lower alkoxyof from 1 to 4 carbon atoms, dimethoxy, trimethoxy, or trifluoromethyl;and R is hydrogen, chlorine, bromine or fluorine.

2. A chemical compound according to claim 1 in which R is hydrogen.

3. A chemical compound according to claim 2 in which R is hydrogen.

4. A chemical compound according to claim 2 in which R and R arehydrogen.

5. A chemical compound according to claim 1 in which R is acrylyl.

6. A chemical compound according to claim 1 in which R is methacrylyl.

7. A chemical compound according to claim 2 in which R is chlorine.

8. A chemical compound according to claim 2 in which R is methyl.

9. A chemical compound according to claim 2 in which R is methoxy.

10. A chemical compound according to claim 5 in which R is hydrogen.

11. A chemical compound according to claim 1 in which R is ethoxy and Ris hydrogen.

References Cited UNITED STATES PATENTS 3,676,464 7/1972 Foden et a1.260- 436 ALEX MAZEL, Primary Examiner A. M. T. TIGHE, Assistant ExaminerUJS. Cl. X.R.

260240 J, 465 D, 465 F, 465 G, 465 H; 424-279

